Evaluating the case-positive, control test-negative study design for influenza vaccine effectiveness for the frailty bias

Publication date: Available online 28 February 2016
Source:Vaccine
Author(s): H. Keipp Talbot, Hui Nian, Qingxia Chen, Yuwei Zhu, Kathryn M. Edwards, Marie R. Griffin
IntroductionPrevious influenza vaccine effectiveness studies were criticized for their failure to control for frailty. This study was designed to see if the test-negative study design overcomes this bias.MethodsAdults≥50 years of age with respiratory symptoms were enrolled from November 2006 through May 2012 during the influenza season (excluding the 2009–2010 H1N1 pandemic season) to perform yearly test-negative control influenza vaccine effectiveness studies in Nashville, TN. At enrollment, both a nasal and throat swab sample were obtained and tested for influenza by RT-PCR. Frailty was calculated using a modified Rockwood Index that included 60 variables ascertained in a retrospective chart review giving a score of 0 to 1. Subjects were divided into three strata: non frail (≤0.08), pre-frail (>0.08 to <0.25), and frail (≥0.25). Vaccine effectiveness was calculated using the formula [1-adjusted odds ratio (OR)]×100%. Adjusted ORs for individual years and all years combined were estimated by penalized multivariable logistic regression.ResultsOf 1023 hospitalized adults enrolled, 866 (84.7%) participants had complete immunization status, molecular influenza testing and covariates to calculate frailty. There were 83 influenza-positive cases and 783 test-negative controls overall, who were 74% white, 25% black, and 59% female. The median frailty index was 0.167 (Interquartile: 0.117, 0.267). The frailty index was 0.167 (0.100, 0.233) for the influenza positive cases compared to 0.183 (0.133, 0.267) for influenza negative controls (p=0.07). Vaccine effectiveness estimates were 55.2% (95%CI: 30.5, 74.2), 60.4% (95%CI: 29.5, 74.4), and 54.3% (95%CI: 28.8, 74.0) without the frailty variable, including frailty as a continuous variable, and including frailty as a categorical variable, respectively.ConclusionsUsing the case positive test negative study design to assess vaccine effectiveness, our measure of frailty was not a significant confounder as inclusion of this measure did not significantly change vaccine effectiveness estimates.



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Does frequent residential mobility in early years affect the uptake and timeliness of routine immunisations? An anonymised cohort study

Publication date: Available online 27 February 2016
Source:Vaccine
Author(s): Hayley A. Hutchings, Annette Evans, Peter Barnes, Melanie A. Healy, Michelle James-Ellison, Ronan A. Lyons, Alison Maddocks, Shantini Paranjothy, Sarah E. Rodgers, Frank Dunstan
BackgroundThere are conflicting findings regarding the impact of residential mobility on immunisation status. Our aim was to determine whether there was any association between residential mobility and take up of immunisations and whether they were delayed in administration.MethodsWe carried out a cohort analysis of children born in Wales, UK. Uptake and time of immunisation were collected electronically. We defined frequent movers as those who had moved: 2 or more times in the period prior to the final scheduled on-time date (4 months) for 5 in 1 vaccinations; and 3 or more times in the period prior to the final scheduled on-time date (12 months) for MMR, pneumococcal and meningitis C vaccinations. We defined immunisations due at 2–4 months delayed if they had not been given by age 1; and those due at 12–13 months as delayed if they had not been given by age 2.ResultsUptake rates of routine immunisations and whether they were given within the specified timeframe were high for both groups. There was no increased risk (odds ratios (95% confidence intervals) between frequent movers compared to non-movers for the uptake of: primary MMR 1.08 (0.88–1.32); booster Meningitis C 1.65 (0.93–2.92); booster pneumococcal 1.60 (0.59–4.31); primary 5 in 1 1.28 (0.92–1.78); and timeliness: primary MMR 0.92 (0.79–1.07); booster Meningitis C 1.26 (0.77–2.07); booster pneumococcal 1.69 (0.23–12.14); and primary 5 in 1 1.04 (0.88–1.23).DiscussionFindings suggest that children who move home frequently are not adversely affected in terms of the uptake of immunisations and whether they were given within a specified timeframe. Both were high and may reflect proactive behaviour in the primary healthcare setting to meet Government coverage rates for immunisation.



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Study on the relationship between miR-520g and the development of breast cancer

OBJECTIVE: Breast cancer (BC) is one of the most common malignant tumors occurred in women. There is no sensitive and specific marker for early diagnosis, treatment and prognosis of breast cancer. It is suggested that miRNA may be a potential tumor marker for breast cancer. Mir-520g is considered to be associated with many tumors. This study aims to test the expression of mir-520g in peripheral blood of BC patients and healthy control. We also explored the relationship between mir-520g and several prognostic factors in breast cancer patients.

PATIENTS AND METHODS: The peripheral blood of 86 cases with breast cancer (including 18 cases with stage 0, 24 cases of phase I, 20 cases of stage II, 24 cases of stage III) and 26 cases of healthy subjects were collected. The miR-520g level was measured by real-time quantitative PCR (RT qPCR) method. The correlation between plasma miR-520g level and the clinical stage, molecular subtype, receptors' expression and other factors related to the prognosis of the patients were examined.

RESULTS: Plasma mir-520g expression levels were significantly higher in BC patients with lymph node metastatic and low differentiation degree grade (p = 0.033 and 0.016), and plasma miR-520g expression was significantly higher in breast cancer patients with mammary gland invasion (p < 0.01) and low expressed p53 (p = 0.0039).

CONCLUSIONS: Highly expressed mir-520g is associated with lymph node metastasis and low differentiation of breast cancer, and also is associated with mammary gland invasion in breast cancer. This study suggests that mir-520g may be associated with some important prognostic factors in breast cancer patients, and may have a potential value for breast cancer marker.

L'articolo Study on the relationship between miR-520g and the development of breast cancer sembra essere il primo su European Review.

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Preoperative neutrophil-to-lymphocyte ratio (NLR) may be predictive of pathologic stage in patients with bladder cancer larger than 3 cm

OBJECTIVE: Bladder cancer (BCa) is the most common malignancy of the urinary tract. In this study, we aimed to evaluate the ability of preoperative neutrophil-to-lymphocyte ratio (NLR) to predict pathologic stage of at the time of first transurethral resection of bladder tumor (TUR-BT) in patients with BCa larger than 3 cm.

PATIENTS AND METHODS: Records of consecutive patients undergoing TUR-BT for BCa with a diameter >3 cm were reviewed. A total of 222 patients were eligible for analysis, and were divided into two groups: 162 patients in non-muscle-invasive BCa (NMIBC) group and 60 patients in muscle-invasive BCa (MIBC) group. Differences in preoperative blood parameters and NLR were evaluated between groups with an unequal variance t-test.

RESULTS: In the NMIBC group, 59 patients had low-grade and 103 high-grade papillary urothelial carcinomas. 60 patients had T2 stage carcinoma. The mean age of the patients was 71.8 and 75.7 years, and mean NLR was 3.44 ± 2.03 and 4.6 ± 2.8 in NMIBC and MIBC groups, respectively. In terms of NLR, there was a statistically significant difference between the NMIBC and MIBC groups (p = 0.005).

CONCLUSIONS: Our results showed that NLR might act as a significant predictive biomarker on the staging of BCa. Also, NLR could be used as a cost-effective, simple, common usable biomarker in urology clinic practice.

L'articolo Preoperative neutrophil-to-lymphocyte ratio (NLR) may be predictive of pathologic stage in patients with bladder cancer larger than 3 cm sembra essere il primo su European Review.

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Expression of CD27, CD28 and IL-17A in peripheral blood from patients with colorectal carcinoma

OBJECTIVE: To compare the different expressions of CD27, CD28, IL-17A, IFN-γ and TNF-α in the peripheral blood sampled from patients with colorectal carcinoma and healthy volunteers.

PATIENTS AND METHODS: Vδ2 T cells were isolated from the peripheral blood mononuclear cells (PBMCs) of patients with the colorectal carcinoma (CRC, n = 30) and healthy controls (HC, n = 21). The proportion of CD27, CD28, IL-17A, IFN-γ and TNF-α of Vδ2 T cells was detected by the flow cytometry.

RESULTS: We found that the proportion of IL-17A of Vδ2 T cells in PBMCs was higher in the CRC vs. the HC group (p < 0.05). A significant positive correlation was observed between the expression of IFN-γ and TNF-α of Vδ2 T cells. In the CRC patients, the proportions of IL-17A of CD27- Vδ2 T cells and CD28+ Vδ2 T cells were higher than those of CD27+ Vδ2 T cells and CD28- Vδ2 T cells, whereas the expression of IFN-γ and TNF-α of CD27-Vδ2 T cells was lower than that of CD27+ Vδ2 T cells.

CONCLUSIONS: Vδ2 T cells from PBMCs had higher expression of IL-17A in CRC patients than that in the HC group. The expression of IFN-γ and TNF-α of Vδ2 T cells from PBMCs was positively correlated. The cytokine profiles of peripheral Vδ2 T cells were likely determined by a CD27 and CD28 involving mechanism.

L'articolo Expression of CD27, CD28 and IL-17A in peripheral blood from patients with colorectal carcinoma sembra essere il primo su European Review.

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Relationship between leptin and regulatory T cells in systemic lupus erythematosus: preliminary results

OBJECTIVE: Crescent literature data demonstrated a role of adipokines in immune responses, particularly leptin is involved in wide spectrum of pro-inflammatory functions. Several evidences suggested that leptin is able to inhibit T regulatory cells proliferation and function in vitro models. In the present study, we investigate the relationship between leptin and circulating T regulatory cells (Tregs) in patients affected by systemic lupus erythematosus (SLE).

PATIENTS AND METHODS: 13 SLE patients and 11 healthy controls were enrolled. Metabolic syndrome and cardiovascular parameters were evaluated. Serum leptin levels were detected by commercial ELISA kit and circulating regulatory T cells were determined by FACS analysis as CD4+CD25highFOP3+ lymphocytes.

RESULTS: Metabolic syndrome, defined by ATPIII criteria, was more prevalent in SLE compared to controls (38.4% vs. 0%, p = 0.04), as well as arterial hypertension (38.4% vs. 0%, p = 0.04). We did not find significant differences in mean leptin levels among SLE and controls (13.13±1.51 ng/ml vs. 9.48±8.67 ng/ml, p = 0.6). Mean Tregs percentage of total CD4 were 1.27±0.9 in SLE vs. 2.8±1.2 in healthy controls (p = 0.001). We found a negative correlation between leptin levels and Tregs percentage of total CD4 in SLE patients (r = 0.4, p = 0.01).

CONCLUSIONS: Our results, suggest a role of leptin in the regulation of circulating T regulatory cells amount in human SLE.

L'articolo Relationship between leptin and regulatory T cells in systemic lupus erythematosus: preliminary results sembra essere il primo su European Review.

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A potential clinical usefulness of measuring serum bilirubin levels in patients with polymyositis

OBJECTIVE: Accumulated data have indicated that bilirubin has antiinflammatory, antioxidative, and immunosuppressive properties. Polymyositis (PM) belongs to an autoimmune disease characterized by chronic inflammation in skeletal muscle. Until now, to the best of our knowledge, there are no literature investigating bilirubin levels in patients with PM. Therefore, the aim of this investigation was to assess a relationship between bilirubin and PM.

PATIENTS AND METHODS: Our study included newly diagnosed 77 patients with PM who were admitted to the Affiliated Hospital of Youjiang Medical University for Nationalities (Guangxi, China) and 108 healthy subjects as controls. Clinical characteristics and laboratory parameters of patients were analyzed, retrospectively.

RESULTS: The serum concentrations of total bilirubin (TB), conjugate bilirubin (CB), unconjugated bilirubin (UCB) were significantly lower in patients with PM than healthy controls. Serum concentrations of TB were negatively correlated with erythrocyte sedimentation rate (ESR), creatine kinase (CK) and lactic dehydrogenase (LDH) in patients with PM (r=-0.494, p＜0.001; r=-0.274, p=0.017; r=-0.282, p=0.014), and serum concentrations of UCB were negatively correlated with ESR and CK in PM patients (r=-0.424, p＜0.001; r=-0.234, p=0.041). Both serum TB and UBC concentrations were positively correlated with manual muscle test (MMT) score in patients with PM (r=0.328, p=0.004; r=0.333, p=0.004). In multiple linear regression analysis, serum UBC levels were independently associated with MMT score (r=0.239, p=0.003).

CONCLUSIONS: We observed significantly lower serum concentrations of TB, CB and UCB in patients with PM, and suggested a potential association between serum concentrations of UBC and disease activity in PM patients.

L'articolo A potential clinical usefulness of measuring serum bilirubin levels in patients with polymyositis sembra essere il primo su European Review.

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The effect of permissive hypotension in combined traumatic brain injury and blunt abdominal trauma: an experimental study in swines

OBJECTIVE: Optimal hemodynamic resuscitation strategy of the trauma patient with uncontrolled hemorrhage and severe head injury in the pre-hospital setting remains a special challenge. Permissive hypotension prior to definite surgical haemostasis promotes coagulation, decreases blood loss and favors survival. However, hypotension is associated with poor outcome in severe head injury. The purpose of this experimental animal study was to assess the impact of permissive hypotension on survival, hemodynamic profile and brain oxygenation parameters before and/or after definite surgical haemostasis.

PATIENTS AND METHODS: Six-week-old pigs (n=12) underwent general anesthesia and brain injury was produced by the fluid percussion model. Animals were instrumented to measure hemodynamic parameters and cerebral blood flow. All animals (n=12) were subjected to laparotomy and a surgical knot was placed through the abdominal aorta wall. Uncontrolled hemorrhage was simulated by pulling out the intentionally left protruding free ends of the suture (goal MAP=30 mmHg). Animals were randomly divided into two groups; group A (n=6) was subjected to aggressive fluid resuscitation (goal SAP >80 mmHg) and group B (n=6) was left hypotensive (permissive hypotension). Animals who survived one hour of hypotensive shock underwent definite surgical haemostasis and were resuscitated for one hour. We measured survival, hemodynamic and brain oxygenation parameters at different time points before and after surgical haemostasis.

RESULTS: All animals from Group A and 50% from Group B died before surgical haemostasis. In surviving animals (Group B, 50%, p=0.033), MAP, CO, rCBF, SjO2 and AVDO2 were restored to pre-procedural levels.

CONCLUSIONS: Permissive hypotension by delaying fluid resuscitation up to definite surgical haemostasis improves survival, hemodynamics and allows restoration of cerebral oxygenation in severe head injury.

L'articolo The effect of permissive hypotension in combined traumatic brain injury and blunt abdominal trauma: an experimental study in swines sembra essere il primo su European Review.

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A new cyclic RGD peptide dimer for integrin αvβ3 imaging

OBJECTIVE: To design a new Arg-Gly-Asp (RGD) peptide that can specifically bind integrin αvβ3 and evaluate the possibility of using 131I-labeled peptide for imaging αvβ3-positive tumors.

MATERIALS AND METHODS: The structure of the RGD monomer was selected using V-life software. Based on the RGD monomer, a dimer of cyclic RGD [c(RGD)2] linked by Tyr-(D)Ser-Lys-(D)Ser-Ser with a Gly-Gly-(D)Ala-Gly side chain on the lysine residue was synthesized. 131I-c(RGD)2 was synthesized using the chloramine-T (ChT) method, and the octanol-water partition coefficient was experimentally measured. To evaluate its binding affinity and selectivity, its equilibrium dissociation constant (Kd) with U87 MG glioma cells was measured in vitro, while whole body imaging and biodistribution were assessed in vivo in mice bearing U87 MG xenografts.

RESULTS: The optimal structure of the monomer was cyclic [-Cys-Arg-Gly-Asp-(D)Ser-Cys-]. The 131I-c(RGD)2 molecule exhibited good stability and was highly hydrophilic. The Kd value was (3.87 ± 0.05) × 10-9 M, suggesting a high αvβ3-binding affinity and specificity. The tumors were clearly visualized at 3 and 6 h post-injection. Biodistribution data of the 131I-c(RGD)2 molecule showed rapid clearance from the blood and predominant accumulation in the tumor and kidney. The tumor-to-normal tissue (T/NT) ratio increased over time. At 24 h post-injection, the tumor-to-liver, tumor-to-muscle, and tumor-to-blood ratios were 4.92, 4.29, and 5.00, respectively.

CONCLUSIONS: These results suggest that the 131I-c(RGD)2 molecule may serve as a promising tracer for the detection of αvβ3-positive tumors.

L'articolo A new cyclic RGD peptide dimer for integrin αvβ3 imaging sembra essere il primo su European Review.

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Impression cytological study for ocular surface disorders of late stage eye burns

OBJECTIVE: This study aims to explore the ocular surface of late stage eye burns by impression cytology (IC) and analyze the cytological changes and their relationship to ocular surface abnormalities.

PATIENTS AND METHODS: 68 eyes with late stage eye burns (thermal burn: 28 eyes; alkali burn: 26 eyes; acid burn: 14 eyes), procured from 68 patients (aged ranges from 17 to 70 years old). Ocular surface abnormalities were assessed under slit lamp and graded. These were broadly classified as eyelid, corneal, conjunctival, and tear film abnormalities. Impression cytological examination was taken by cellulose acetate filter paper for all eyes. Samples were analyzed and scored under light microscope, including the status of epithelial cells, goblet cells, mucus and inflammatory cells. All the results and data were compared and analyzed by SPSS software (version 16.0).

RESULTS: According to the IC results, loosed cell-to-cell density and nuclear abnormality, keratinization, reduced goblet cell amount, disorder of mucus, and existing of inflammatory cells were observed in almost all the cases. The IC results were significantly correlated to the ocular surface injury severity (r=0.458, p<0.01). The ocular surface injury severity mostly contains three aspects: the corneal neovascularization scales, the present or absent of recurrent epithelial erosion and the tear film break-up time. Eyes with the foreword three symptoms were inclined to have higher IC scores. The epithelial cell-to-cell density, goblet cell and mucus amount were all correlated to tear film break-up time. However, inflammatory cell density showed no significant correlation to the conjunctival hyperemia grade. But inflammatory cell density correlated to the corneal opacity grade and epithelial stability status.

CONCLUSIONS: IC examinations could reflect the cytological disorders and relative injury severity of the ocular surface in late stage eye burns. It provides further information which will be useful in surgery and therapy.

L'articolo Impression cytological study for ocular surface disorders of late stage eye burns sembra essere il primo su European Review.

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A correlation between selenium and carnitine levels with Hypo-osmotic swelling test for sperm membrane in low-grade varicocele patients

OBJECTIVE: The hypo-osmotic swelling (HOS) test predicts membrane integrity by determining the ability of the sperm membrane to maintain equilibrium between the sperm cell and its environment. The aim of our study was to determine the correlation between selenium and carnitine levels in the seminal fluid with HOS test for sperm membrane in low-grade varicocele patients.

PATIENTS AND METHODS: Study numbered 64 examinees who suffered from low-grade varicocele and were divided into two groups, according to fertility potential and HOS test outcome. The study also included a control group of 64 healthy subjects, with no varicocele.

RESULTS: From the Shapiro-Wilk's test, it is clear that carnitine distribution differs significantly from normal (0.938, p = 0.03). In distribution of selenium, Kolmogorov-Smirnov test clearly shows statistically significant deviation from the normal curve (z = 0.225, p < 0.000), likewise Shapiro-Wilk's statistic (0.787, p < 0.000). According to the results, the second group had significantly higher levels of carnitine and selenium than the first group of examinees (p < 0.05); therefore, when we compared epididymal markers with HOS tests outcomes, we found significant differences between the two groups. There were no significant differences between second group and healthy subjects (p > 0.05).

CONCLUSIONS: HOS test outcome in varicocele patients is directly proportional to the carnitine and selenium levels, which could play a major role in both determining fertility parameters and in the treatment of its impairment. This result is especially important for sub-clinical varicocele in infertile patients with normal semen analysis, since there is no evidence of benefit from any treatment so far.

L'articolo A correlation between selenium and carnitine levels with Hypo-osmotic swelling test for sperm membrane in low-grade varicocele patients sembra essere il primo su European Review.

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Effect of complete hilar versus only renal artery clamping on renal histomorphology following ischemia/reperfusion injury in an experimental model

OBJECTIVE: To evaluate the effect of temporary complete hilar versus only renal artery clamping with different duration of warm ischemia on renal functions, and possibly identify a "safe" clamping type and duration of renal ischemia.

MATERIALS AND METHODS: Fifty male rabbits have been incorporated to study. Rabbits were subjected to ischemia/reperfusion injury by temporary vascular clamping. Reagents were randomized to 3 experimental groups (only renal artery clamping, complete hilar clamping, sham surgery) and sub-groups were determined according to different clamping times (30 and 60 minutes). Median laparotomy and left renal hilus dissection were performed to sham group. Only artery or complete hilar clamping was performed for 30 or 60 minutes by microvascular bulldog clamps to other reagents. Rabbits were sacrificed 10 days after primary surgery and left nephrectomy performed. Nephrectomy materials were evaluated for the level of nitric-oxide synthase (NOS) immunoreactivity, malondialdehyde (MDA) level and superoxide dismutase (SOD) activity and an electron microscopic examination was performed.

RESULTS: NOS immunoreactivity was correlated with the temporary clamping time. We also observed that complete hilar vascular clamping entails an increase on NOS immunoreactivity. MDA levels were similar for all experimental surgery groups (p = 0.42). The SOD activity was decreased among all subgroups compared with sham surgery. But the significant decrease occurred in 30 minutes only artery and 30 minutes complete hilar clamping groups in proportion to sham surgery (p = 0.026 and p = 0.019, respectively).

CONCLUSIONS: This current study suggested that only renal artery clamping under 30 minutes is more appropriate during renal surgical procedures requiring temporary vascular clamping.

L'articolo Effect of complete hilar versus only renal artery clamping on renal histomorphology following ischemia/reperfusion injury in an experimental model sembra essere il primo su European Review.

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Mutations reducing replication from R-loops suppress the defects of growth, chromosome segregation and DNA supercoiling in cells lacking topoisomerase I and RNase HI activity

Publication date: Available online 27 February 2016
Source:DNA Repair
Author(s): Valentine Usongo, Makisha Martel, Aurélien Balleydier, Marc Drolet
R-loop formation occurs when the nascent RNA hybridizes with the template DNA strand behind the RNA polymerase. R-loops affect a wide range of cellular processes and their use as origins of replication was the first function attributed to them. In E. coli, R-loop formation is promoted by the ATP-dependent negative supercoiling activity of gyrase (gyrA and gyrB) and is inhibited by topoisomerase (topo) I (topA) relaxing transcription-induced negative supercoiling. RNase HI (rnhA) degrades the RNA moiety of R-loops. The depletion of RNase HI activity in topA null mutants was previously shown to lead to extensive DNA relaxation, due to DNA gyrase inhibition, and to severe growth and chromosome segregation defects that were partially corrected by overproducing topo III (topB). Here, DNA gyrase assays in crude cell extracts showed that the ATP-dependent activity (supercoiling) of gyrase but not its ATP-independent activity (relaxation) was inhibited in topA null cells lacking RNase HI. To characterize the cellular event(s) triggered by the absence of RNase HI, we performed a genetic screen for suppressors of the growth defect of topA rnhA null cells. Suppressors affecting genes in replication (holC2:aph and dnaT18:aph) nucleotide metabolism (dcd49:aph), RNA degradation (rne59:aph) and fimbriae synthesis (fimD22:aph) were found to reduce replication from R-loops and to restore supercoiling, thus pointing to a correlation between R-loop-dependent replication in topA rnhA mutants and the inhibition of gyrase activity and growth. Interestingly, the position of fimD on the E. coli chromosome corresponds to the site of one of the five main putative origins of replication from R-loops in rnhA null cells recently identified by next-generation sequencing, thus suggesting that the fimD22:aph mutation inactivated one of these origins. Furthermore, we show that topo III overproduction is unable to complement the growth defect of topA rnhA null mutants at low temperatures that stabilizes hyper-negatively supercoiled DNA.



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Cross-Modal Transfer of Statistical Information Benefits from Sleep

Publication date: Available online 27 February 2016
Source:Cortex
Author(s): Simon J. Durrant, Dr Scott A. Cairney, Dr Penelope A. Lewis
Extracting regularities from a sequence of events is essential for understanding our environment. However, there is no consensus regarding the extent to which such regularities can be generalised beyond the modality of learning. One reason for this could be the variation in consolidation intervals used in different paradigms, also including an opportunity to sleep. Using a novel statistical learning paradigm in which structured information is acquired in the auditory domain and tested in the visual domain over either 30min or 24hr consolidation intervals, we show that cross-modal transfer can occur, but this transfer is only seen in the 24hr group. Importantly, the extent of cross-modal transfer is predicted by the amount of SWS obtained. Additionally, cross-modal transfer is associated with the same pattern of decreasing MTL and increasing striatal involvement which has previously been observed to occur across 24 hours in unimodal statistical learning. We also observed enhanced functional connectivity after 24 hours in a network of areas which have been implicated in cross-modal integration including the precuneus and the middle occipital gyrus. Finally, functional connectivity between the striatum and the precuneus was also enhanced, and this strengthening was predicted by SWS. These results demonstrate that statistical learning can generalise to some extent beyond the modality of acquisition, and together with our previously published unimodal results, support the notion that statistical learning is both domain-general and domain-specific.



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Editorial Board/Title Page

Publication date: March 2016
Source:Cortex, Volume 76





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Contralesional distractors enhance ipsilesional target processing after right-hemispheric stroke

Publication date: Available online 27 February 2016
Source:Cortex
Author(s): Simone Vossel, Gereon R. Fink
Stroke can result in marked impairments in the processing of information presented in contralesional space. The present prospective study investigated how a contralesional distractor affects ipsilesional perception in patients with a right-hemispheric stroke. In a simple target detection task, the influence of the distractor on reaction times was examined in stroke patients and compared to the performance of healthy elderly controls. Distractor interference effects were related to measures of neglect and extinction using a regression analysis. Moreover, the magnitude of the behavioural distractor effect entered a voxel-based lesion-symptom mapping analysis with the hypothesis that parietal and temporoparietal lesions are related to altered distractor processing. While the presence of a distractor in the opposite hemifield slowed down reaction times in healthy controls for left and right targets, this effect was only observed for contralesional left targets in the group of right-hemispheric patients. In stark contrast, the presence of a distractor in the contralesional hemifield expedited ipsilesional (i.e., right) target detection. This effect was significantly related to lesions in the anterior middle temporal and temporoparietal cortex, external and internal capsule, as well as the superior longitudinal fascicle. These results elucidate the nature of the disruption of attentive processing in the contralesional hemifield after right-hemispheric stroke. More specifically, they shed light on the abnormal prioritisation of ipsilesional information: our data suggest that damage to the temporal and temporoparietal cortex and white matter tracts may transform contralesional stimulation into an unspecific saliency signal contributing to facilitated information processing in ipsilesional space.



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A third-person perspective on co-speech action gestures in Parkinson’s disease

Publication date: Available online 27 February 2016
Source:Cortex
Author(s): Stacey Humphries, Judith Holler, Trevor J. Crawford, Elena Herrera, Ellen Poliakoff
A combination of impaired motor and cognitive function in Parkinson's disease (PD) can impact on language and communication, with patients exhibiting a particular difficulty processing action verbs. Co-speech gestures embody a link between action and language and contribute significantly to communication in healthy people. Here, we investigated how co-speech gestures depicting actions are affected in PD, in particular with respect to the visual perspective—or the viewpoint – they depict. Gestures are closely related to mental imagery and motor simulations, but people with PD may be impaired in the way they simulate actions from a first-person perspective and may compensate for this by relying more on third-person visual features. We analysed the action-depicting gestures produced by mild-moderate PD patients and age-matched controls on an action description task and examined the relationship between gesture viewpoint, action naming, and performance on an action observation task (weight judgement). Healthy controls produced the majority of their action gestures from a first-person perspective, whereas PD patients produced a greater proportion of gestures produced from a third-person perspective. We propose that this reflects a compensatory reliance on third-person visual features in the simulation of actions in PD. Performance was also impaired in action naming and weight judgement, although this was unrelated to gesture viewpoint. Our findings provide a more comprehensive understanding of how action-language impairments in PD impact on action communication, on the cognitive underpinnings of this impairment, as well as elucidating the role of action simulation in gesture production.



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Role of features and categories in the organization of object knowledge: Evidence from adaptation fMRI

Publication date: Available online 6 February 2016
Source:Cortex
Author(s): Jingyi Geng, Tatiana T. Schnur
There are two general views regarding the organization of object knowledge. The feature-based view assumes that object knowledge is grounded in a widely distributed neural network in terms of sensory/function features (e.g., Warrington & Shallice, 1984), while the category-based view assumes in addition that object knowledge is organized by taxonomic and thematic categories (e.g., Schwartz et al., 2011). Using an functional magnetic resonance imaging (fMRI) adaptation paradigm, we compared predictions from the feature- and category-based views by examining the neural substrates recruited as subjects read word pairs that were identical, taxonomically related, thematically related or unrelated while controlling for the function features involved across the two categories. We improved upon previous study designs and employed an fMRI adaptation task, obtaining results overall consistent with both the category-based and feature-based views. Consistent with the category-based view, we observed for both hypothesized regions of interest (ROI) and exploratory (whole-brain analyses) reduced activity in the left anterior temporal lobe (ATL) for taxonomically related versus unrelated word pairs, and for the exploratory analysis only, reduced activity in the right ATL. In addition, the exploratory analyses revealed reduced activity in the left temporo-parietal junction (TPJ) for thematically related versus unrelated word pairs. Consistent with the feature-based view, we found in the exploratory analyses that activity in the bilateral precentral gyri (i.e., function regions) including part of premotor cortex reduced as the function relatedness ratings increased. However, we did not find a relationship between adaptation effects in the bilateral ATLs and left TPJ and corresponding ratings of taxonomic/thematic relationships suggesting that the adaptation effects may potentially not reflect aspects of taxonomy that have been traditionally assumed. Together, our findings indicate that both feature and category information are important for the organization of object knowledge although the exact nature of those organization principles is an important question for future research.



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Emotional caricatures in frontotemporal dementia

Publication date: March 2016
Source:Cortex, Volume 76
Author(s): Camilla N. Clark, Jason D. Warren




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Cover Figure

Publication date: March 2016
Source:Cortex, Volume 76





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Should People with Patent Foramen Ovale Go to High Altitude? A Case Report of an Alpinist with a Patent Foramen Ovale Exposed to Extreme Altitude

High Altitude Medicine & Biology , Vol. 0, No. 0.


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Naproxen, a Nonsteroidal Anti-Inflammatory Drug Can Affect Daily Hypobaric Hypoxia-Induced Alterations of Monoamine Levels in Different Areas of the Brain in Male Rats

High Altitude Medicine & Biology , Vol. 0, No. 0.


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Dietary Luteolin Reduces Proinflammatory Microglia in the Brain of Senescent Mice

Rejuvenation Research , Vol. 0, No. 0.


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Racemized and Isomerized Proteins in Aging Rat Teeth and Eye Lens

Rejuvenation Research , Vol. 0, No. 0.


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A Rat Treated with Mesenchymal Stem Cells Lives to 44 Months of Age

Rejuvenation Research , Vol. 0, No. 0.


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Effect of Zhuang Jing Decoction on Learning and Memory Ability in Aging Rats

Rejuvenation Research , Vol. 0, No. 0.


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Novel Food Supplement “CP1” Improves Motor Deficit, Cognitive Function, and Neurodegeneration in Animal Model of Parkinson's Disease

Rejuvenation Research , Vol. 0, No. 0.


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Change in the Multidimensional Prognostic Index Score During Hospitalization in Older Patients

Rejuvenation Research , Vol. 0, No. 0.


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Values in Elderly People for Exhaled Nitric Oxide Study

Rejuvenation Research , Vol. 0, No. 0.


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Rejuvenation Research Feb 2016, Vol. 19, No. 1: 100-104.

Rejuvenation Research Feb 2016, Vol. 19, No. 1: 100-104.


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Commentary on Some Recent Theses Relevant to Combating Aging: February 2016

Rejuvenation Research Feb 2016, Vol. 19, No. 1: 94-99.


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Aging of Stem and Progenitor Cells: Mechanisms, Impact on Therapeutic Potential, and Rejuvenation

Rejuvenation Research Feb 2016, Vol. 19, No. 1: 3-12.


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How Can We Make the Health Span Focus of Biomedical Gerontology “Stickier”?

Rejuvenation Research Feb 2016, Vol. 19, No. 1: 1-2.


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Thymus Maintenance and Regeneration by Specific Molecular Factors

Rejuvenation Research Feb 2016, Vol. 19, No. 1: 90-93.


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Diabetes and Age-Related Differences in Vascular Function of Renal Artery: Possible Involvement of Endoplasmic Reticulum Stress

Rejuvenation Research Feb 2016, Vol. 19, No. 1: 41-52.


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Serum- and Glucocorticoid-Inducible Kinase 1 Delay the Onset of Endothelial Senescence by Directly Interacting with Human Telomerase Reverse Transcriptase

Rejuvenation Research Feb 2016, Vol. 19, No. 1: 79-89.


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Increased Physical Activity and Fitness above the 50th Percentile Avoid the Threat of Older Adults Becoming Institutionalized: A Cross-sectional Pilot Study

Rejuvenation Research Feb 2016, Vol. 19, No. 1: 13-20.


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Effect of Low-Magnitude, High-Frequency Vibration Treatment on Retardation of Sarcopenia: Senescence-Accelerated Mouse-P8 Model

Rejuvenation Research , Vol. 0, No. 0.


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Higher Cognitive Function in Elderly Individuals with Previous Cataract Surgery: Cross-Sectional Association Independent of Visual Acuity in the HEIJO-KYO Cohort

Rejuvenation Research , Vol. 0, No. 0.


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Multi-Axis Soft Sensors Based on Dielectric Elastomer

Soft Robotics , Vol. 0, No. 0.


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Dysplasie de bas grade sur une biopsie : que faire ?

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Lésion néoplasique superficielle : comment choisir entre chirurgie, mucosectomie, dissection sous-muqueuse ?

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Comment bien explorer un estomac en endoscopie (étapes, durée, colorations, iconographie…) ?

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Three-dimensional Particle Tracking Velocimetry for Turbulence Applications: Case of a Jet Flow

A three-dimensional particle tracking velocimetry (3D-PTV) system based on a high-speed camera with a four-view splitter is described here. The technique is applied to a jet flow from a circular pipe in the vicinity of ten diameters downstream at Reynolds number Re ≈ 7,000.

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Full title with Editorial board members

Publication date: March 2016
Source:International Journal of Psychophysiology, Volume 101





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Instructions to Authors

Publication date: March 2016
Source:International Journal of Psychophysiology, Volume 101





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IOP-details

Publication date: March 2016
Source:International Journal of Psychophysiology, Volume 101





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Deacetylation Assays to Unravel the Interplay between Sirtuins (SIRT2) and Specific Protein-substrates

This protocol describes the required steps to execute in vitro and in vivo deacetylation assays in order to establish the role of proteins as specific deacetylation substrates for sirtuins and further study the role of reversible - lysine acetylation as a post-translational modification.

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Synthesis of Poly(N-isopropylacrylamide) Janus Microhydrogels for Anisotropic Thermo-responsiveness and Organophilic/Hydrophilic Loading Capability

We present a protocol to synthesize Janus microhydrogels composed entirely of the same base material, poly(N-isopropylacrylamide) (PNIPAAm), with a clearly compartmentalized structure base on the phase separation of a supersaturated NIPAAm monomer solution. The synthesized Janus microhydrogels show unique properties such as anisotropic thermo-responsiveness and organophilic/hydrophilic loading capability.

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Fetal left modified myocardial performance index measured by the Auto Mod-MPI system: development of reference values and application to recipients of twin-to-twin transfusion syndrome

Abstract

Objectives

To establish normal reference ranges for the fetal left modified myocardial performance index (Mod-MPI) measured by the Auto Mod-MPI system and evaluate Mod-MPI changes in recipients of twin-to-twin transfusion syndrome (TTTS) before and after fetoscopic laser coagulation. This article is protected by copyright. All rights reserved.

Methods

This was a prospective longitudinal study of normal singleton fetuses from 12.0 to 40.0 weeks of gestation. TTTS cases treated by laser coagulation were reviewed for Mod-MPI measurements of recipients. All measurements were performed using the Auto Mod-MPI system by a single experienced operator.

Results

Among a total 447 examinations from 222 fetuses, we were unable to measure the Mod-MPI in two cases, and therefore, 445 examinations were analyzed. The median Mod-MPI consistently increased from 0.44 to 0.56 throughout gestation. The median isovolumetric contraction time (ICT) and isovolumetric relaxation time (IRT) also increased with advancing gestational age. The ejection time (ET) increased until 27 weeks of gestation and decreased thereafter. In the 30 recipients, Mod-MPI, ICT, and IRT increased before laser coagulation and significantly decreased after laser coagulation.

Conclusion

Normal reference values for left Mod-MPI were established using the Auto Mod-MPI system and these might be useful for assessing cardiac function in TTTS.

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Non-Ventilator ICU-Acquired Pneumonia After Cardiothoracic Surgery: Accuracy of Diagnostic Tools and Outcomes

BACKGROUND:Non-ventilator ICU-acquired pneumonia after cardiothoracic surgery is challenging to diagnose, and little is known about its impact on patient outcomes. Here, our primary objective was to compare the sensitivity and specificity of cultures of 2 types of fiberoptic bronchoscopy (FOB) specimens: endotracheal aspirates (FOB-EA) and bronchoalveolar lavage fluid (FOB-BAL). The secondary objectives were to evaluate the sensitivity and specificity of spontaneous sputum cultures and of the modified Clinical Pulmonary Infection Score (CPIS) and to describe patient outcomes.METHODS:We conducted a prospective observational study of consecutive cardiothoracic surgery subjects with suspected non-ventilator ICU-acquired pneumonia. Using FOB-BAL cultures ≥104 cfu/mL as the reference standard, we evaluated the accuracy of FOB-EA ≥105 cfu/mL and spontaneous sputum ≥107 cfu/mL. On the day of FOB, we determined the modified CPIS. Mortality and antibiotic treatments were recorded.RESULTS:Of 105 subjects, 57 (54.3%) received a diagnosis of non-ventilator ICU-acquired pneumonia. FOB-EA cultures had 82% (95% CI 69–91%) sensitivity and 100% (95% CI 89–100%) specificity and were significantly less sensitive than FOB-BAL cultures (P < .004). Spontaneous sputum was obtained from one-third of subjects. Spontaneous sputum cultures had 82% (95% CI 56–95%) sensitivity and 94% (95% CI 68–100%) specificity and were non-significantly less sensitive than FOB-BAL (P = .061). A modified CPIS >6 had 42% (95% CI 29–56%) sensitivity and 87% (95% CI 74–95%) specificity for non-ventilator ICU-acquired pneumonia. Antibiotic therapy was stopped in all subjects without non-ventilator ICU-acquired pneumonia, after 1.6 ± 1.2 d, without deleterious effects.CONCLUSIONS:The modified CPIS has low diagnostic accuracy for non-ventilator ICU-acquired pneumonia. FOB-EA cultures perform less well than do FOB-BAL cultures for diagnosing non-ventilator ICU-acquired pneumonia. Spontaneous sputum is valuable when FOB cannot be performed but could be obtained in only a minority of subjects. When cultures are negative, antibiotic discontinuation is safe.

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Configuration of Aerosol Delivery Devices and Their Placement: Let's Be Sure We're Paying Attention to the Literature

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Evaluating the Effect of Flow and Interface Type on Pressures Delivered With Bubble CPAP in a Simulated Model

BACKGROUND:Bubble CPAP, used for spontaneously breathing infants to avoid intubation or postextubation support, can be delivered with different interface types. This study compared the effect that interfaces had on CPAP delivery. We hypothesized that there would be no difference between set and measured levels between interface types.METHODS:A validated preterm infant nasal airway model was attached to the ASL 5000 breathing simulator. The simulator was programmed to deliver active breathing of a surfactant-deficient premature infant with breathing frequency at 70 breaths/min inspiratory time of 0.30 s, resistance of 150 cm H2O/L/s, compliance of 0.5 mL/cm H2O, tidal volume of 5 mL, and esophageal pressure of −10 cm H2O. Nasal CPAP prongs, size 4030, newborn and infant RAM cannulas were connected to a nasal airway model and a bubble CPAP system. CPAP levels were set at 4, 5, 6, 7, 8, and 9 cm H2O with flows of 6, 8, and 10 L/min each. Measurements were recorded after 1 min of stabilization. The analysis was performed using SAS 9.4. The Kolmogorov-Smirnov test assessed normality of the data. The Friedman test was used to compare non-normally distributed repeated measures. The Wilcoxon signed-rank test was used to conduct post hoc analysis. All tests were 2-sided, and P values of <.05 were considered as indicating significant differences unless otherwise indicated.RESULTS:At lower set CPAP levels, 4–6 cm H2O, measured CPAP dropped precipitously with the nasal prongs with the highest flow setting. At higher CPAP levels, 7–9 cm H2O measured CPAP concomitantly increased as the flow setting increased. Statistically significant differences in set and measured CPAP occurred for all devices across all CPAP levels, with the measured CPAP less than set for all conditions, P < .001.CONCLUSIONS:Set flow had a profound effect on measured CPAP. The concomitant drop in measured pressure with high and low flows could be attributed to increased resistance to spontaneous breathing or insufficient flow to meet inspiratory demand. Clinicians should be aware of the effect that the interface and flow have on CPAP delivery.

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Investigation on the ability of first trimester glycodelin and angiopoietin-2 to predict small-for-gestational age pregnancies at delivery

Journal Name: Clinical Chemistry and Laboratory Medicine (CCLM)
Issue: Ahead of print


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Identity Efficiency for High-Performance Ambient Pressure Ion Mobility Spectrometry

Analytical Chemistry

DOI: 10.1021/acs.analchem.5b03765

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Site-Specific Quantification of Surface N-Glycoproteins in Statin-Treated Liver Cells

Analytical Chemistry

DOI: 10.1021/acs.analchem.5b04871

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Vacuum Ultraviolet Photodissociation and Fourier Transform–Ion Cyclotron Resonance (FT-ICR) Mass Spectrometry: Revisited

Analytical Chemistry

DOI: 10.1021/acs.analchem.6b00148

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The Dorsal Scapular Nerve - Everything You Need To Know - Dr. Nabil Ebraheim

Educational video describing the anatomy of the dorsal scapular nerve.

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A Sporadic Neonatal Case of Epidermolysis Bullosa Simplex Generalized Intermediate with KRT5 and KRT14 Gene Mutations

AJP Rep 2016; 06: e108-e111
DOI: 10.1055/s-0035-1570386

Background Epidermolysis bullosa simplex (EBS) is a rare genodermatosis resulting from multiple gene mutations, including KRT5 and KRT14. The clinical expression of the mechanobullous skin fragility disease has not been fully explained by the genotype. Case Description An 11-day-old Japanese newborn infant was hospitalized because of herpetiform skin blistering on the feet, which expanded systemically after birth. There was no evidence of virus infection. The biopsied skin lesion showed a blister on the lamina densa without keratin clumps, indicating a diagnosis of EBS-generalized intermediate. We punctured the blisters to remove the contents daily, which led to no exacerbation or infection. The genetic study determined that the patient carried double substitutions of KRT5 c.1424A > G (p.E475G) and KRT14 c.1237G > A (p.A413T). The asymptomatic mother and sister carried the KRT14 substitution, but the healthy father had no substitution of the KRT gene. Conclusion This is the first report of EBS-generalized intermediate in a newborn with de novo KRT5 gene mutation and KRT14 gene polymorphism, and no familial history of epidermolysis. Neonatal blistering due to EBS requires optimal skin management after excluding infectious and immunobullous diseases.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Article in Thieme eJournals:
Table of contents  |  Abstract  |  open access Full text

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Septo-Optic Dysplasia in a Newborn Presenting with Bilateral Dilated and Fixed Pupils

AJP Rep 2016; 06: e112-e114
DOI: 10.1055/s-0036-1571330

Introduction We describe a newborn female infant with septo-optic dysplasia (SOD) presenting with bilateral dilated and fixed pupils. Conclusion Our report is unique because the incidental finding of bilateral dilated and fixed pupils on the newborn exam was the only clinical finding which led to a prompt work-up and eventual diagnosis of SOD.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Article in Thieme eJournals:
Table of contents  |  Abstract  |  open access Full text

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Consensus Definitions for Sepsis and Septic Shock

This video presents updated definitions of and clinical criteria for diagnosing sepsis and septic shock based on recommendations from an expert task force. Learn more at http://jamasepsis.com.

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Retrospective study of prenatal ultrasound findings in newborns with a Noonan spectrum disorder

Abstract

Objectives

Noonan spectrum disorders (NSDs) occur in 1:1,000-2,500 live births. Currently, there are no guidelines for prenatal molecular genetic testing for NSDs. Recent studies recommend prenatal testing for NSDs when ultrasonography detects two or more associated abnormalities. A stronger association between ultrasound findings and NSDs would enable more informed prenatal genetic testing. This article is protected by copyright. All rights reserved.

Methods

212 newborns (0-12 weeks) with prenatal ultrasound findings and a clinical suspicion of a NSD were referred for molecular genetic testing. Of these, 159/212 newborns tested had a single ultrasound abnormality and 53/212 newborns had two or more. Testing was performed by either a microarray-based resequencing assay or next generation sequencing of RAS/MAPK pathway genes associated with NSDs. Prenatal ultrasound findings in positive and negative cases were compared.

Results

A disease-causing variant was identified in 21.7% (46/212) of newborns tested. Of these positive cases, 67.4% (31/46) had only one ultrasound abnormality reported. The rate of detecting a disease-causing variant in cases with one ultrasound finding was 19.5% (31/159), which was not significantly different (p-value =0.36) than that in cases with two or more ultrasound findings (28.3%; 15/53).

Conclusions

Prenatal molecular testing for NSDs should be considered even in the presence of a single associated abnormal ultrasound finding.

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Imaging Serotonergic Fibers in the Mouse Spinal Cord Using the CLARITY/CUBIC Technique

Supraspinal projections are important for pain perception and other behaviors, and serotonergic fibers are one of these fiber systems. The present study focused on the application of the combined CLARITY/CUBIC protocol to the mouse spinal cord in order to investigate the termination of these serotonergic fibers.

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Determination of Photoreceptor Cell Spectral Sensitivity in an Insect Model from In Vivo Intracellular Recordings

The electrophysiological technique of intracellular recording is demonstrated and used to determine spectral sensitivities of single photoreceptor cells in the compound eye of a butterfly.

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A Vacuum Ultraviolet Absorption Array Spectrometer as a Selective Detector for Comprehensive Two-Dimensional Gas Chromatography: Concept and First Results

Analytical Chemistry

DOI: 10.1021/acs.analchem.5b02472

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Technical Note: Preferred dosimeter size and associated correction factors in commissioning high dose per pulse, flattening filter free x-ray beams

Purpose:

High dose rate flattening filter free (FFF) beams pose new challenges and considerations for accurate reference and relative dosimetry. The authors report errors associated with commonly used ion chambers and introduce simple methods to mitigate them.

Methods:

Dosimetric errors due to (1) ion recombination effects of high dose per pulse (DPP) FFF beams and (2) volume-averaging effects of the radial profile were examined on a TrueBeam STx. Four commonly used cylindrical ion chambers spanning a range of lengths (0.29–2.3 cm) and volumes (0.016–0.6 cm³) were used to determine the magnitude of these effects for 6 and 10 MV unflattened x-ray beams (6XFFF and 10XFFF, respectively). Two methods were used to determine the magnitude of ion collection efficiency: (1) direct measurement of the percent depth dose (PDD) for the clinical, high DPP beam in comparison to that obtained after reducing the DPP and (2) measurement of Pion as a function of depth. Two methods were used to quantify the magnitude of volume-averaging: (1) direct measurement of volume-averaging via cross-calibration and (2) calculation of volume-averaging from radial profiles of the beam. Finally, a simple analytical expression for the radial profile volume-averaging correction factor, Prp = [OAR(0.29L)]⁻¹, or the inverse of the off-axis ratio of dose at 0.29L, where L is the length of the chamber's sensitive volume, is introduced to mitigate the volume-averaging effect in Farmer-type chambers.

Results:

Errors in measured PDD for the clinical beams were 1.3% ± 0.07% and 1.6% ± 0.07% at 35 cm depth for the 6XFFF and 10XFFF beam, respectively, using an IBA CC13 ion chamber, due to charge recombination with a high DPP. Volume-averaging effects were 0.4% and 0.7% for the 6XFFF and 10XFFF beam, respectively, when measured with a Farmer-type chamber. For the application of TG-51, these errors combine when using a CC13 to measure the PDD and a Farmer for absolute output dosimetry for a total error of up to 2% at dmax for the 10XFFF beam.

Conclusions:

Relative and absolute dosimetry in high DPP, unflattened x-ray beams of 10 MV or higher requires corrections for charge recombination and/or volume-averaging when dosimeters with certain geometries are used. Chambers used for PDD measurement are available that do not require a correction for charge recombination. A simple analytical expression of the correction factor Prp was introduced in this work to account for volume-averaging effects in Farmer chambers. Choice of an appropriate dosimeter coupled with application of the established correction factors Pion and Prp reduces the uncertainty in the PDD measurement and the reference dose measurement.

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Application of systems and control theory-based hazard analysis to radiation oncology

Purpose:

Both humans and software are notoriously challenging to account for in traditional hazard analysis models. The purpose of this work is to investigate and demonstrate the application of a new, extended accident causality model, called systems theoretic accident model and processes (STAMP), to radiationoncology. Specifically, a hazard analysis technique based on STAMP, system-theoretic process analysis (STPA), is used to perform a hazard analysis.

Methods:

The STPA procedure starts with the definition of high-level accidents for radiationoncology at the medical center and the hazards leading to those accidents. From there, the hierarchical safety control structure of the radiationoncology clinic is modeled, i.e., the controls that are used to prevent accidents and provide effective treatment. Using STPA, unsafe control actions (behaviors) are identified that can lead to the hazards as well as causal scenarios that can lead to the identified unsafe control. This information can be used to eliminate or mitigate potential hazards. The STPA procedure is demonstrated on a new online adaptive cranial radiosurgery procedure that omits the CT simulation step and uses CBCT for localization, planning, and surface imaging system during treatment.

Results:

The STPA procedure generated a comprehensive set of causal scenarios that are traced back to system hazards and accidents. Ten control loops were created for the new SRS procedure, which covered the areas of hospital and department management, treatment design and delivery, and vendor service. Eighty three unsafe control actions were identified as well as 472 causal scenarios that could lead to those unsafe control actions.

Conclusions:

STPA provides a method for understanding the role of management decisions and hospital operations on system safety and generating process design requirements to prevent hazards and accidents. The interaction of people, hardware, and software is highlighted. The method of STPA produces results that can be used to improve safety and prevent accidents and warrants further investigation.

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Quantifying Fish Swimming Behavior in Response to Acute Exposure of Aqueous Copper Using Computer Assisted Video and Digital Image Analysis

Measuring the impacts of environmental contaminants on fish behavior is often subjective and challenging particularly when dealing with sublethal endpoints. We describe methods including video technology to quantify swimming behavior of early life stage white sturgeon (Acipenser transmontanus) during and after 96 hr acute exposures to various concentrations of copper.

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Domperidone, Parkinson disease and sudden cardiac death: Mice and men show the way

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The influence of (central) auditory processing disorder on the severity of speech-sound disorders in children

OBJECTIVE: To identify a cutoff value based on the Percentage of Consonants Correct-Revised index that could indicate the likelihood of a child with a speech-sound disorder also having a (central) auditory processing disorder . METHODS: Language, audiological and (central) auditory processing evaluations were administered. The participants were 27 subjects with speech-sound disorders aged 7 to 10 years and 11 months who were divided into two different groups according to their (central) auditory processing evaluation results. RESULTS: When a (central) auditory processing disorder was present in association with a speech disorder, the children tended to have lower scores on phonological assessments. A greater severity of speech disorder was related to a greater probability of the child having a (central) auditory processing disorder. The use of a cutoff value for the Percentage of Consonants Correct-Revised index successfully distinguished between children with and without a (central) auditory processing disorder. CONCLUSIONS: The severity of speech-sound disorder in children was influenced by the presence of (central) auditory processing disorder. The attempt to identify a cutoff value based on a severity index was successful.

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Comparison between refraction measured by Spot Vision ScreeningTM and subjective clinical refractometry

OBJECTIVE: The purpose of this study was to evaluate the accuracy of Spot Vision ScreeningTM as an autorefractor by comparing refraction measurements to subjective clinical refractometry results in children and adult patients. METHODS: One-hundred and thirty-four eyes of 134 patients were submitted to refractometry by Spot and clinical refractometry under cycloplegia. Patients, students, physicians, staff and children of staff from the Hospital das Clínicas (School of Medicine, University of São Paulo) aged 7-50 years without signs of ocular disease were examined. Only right-eye refraction data were analyzed. The findings were converted in magnitude vectors for analysis. RESULTS: The difference between Spot Vision ScreeningTM and subjective clinical refractometry expressed in spherical equivalents was +0.66±0.56 diopters (D), +0.16±0.27 D for the vector projected on the 90 axis and +0.02±0.15 D for the oblique vector. CONCLUSIONS: Despite the statistical significance of the difference between the two methods, we consider the difference non-relevant in a clinical setting, supporting the use of Spot Vision ScreeningTM as an ancillary method for estimating refraction.

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Clinical evaluation, biochemistry and genetic polymorphism analysis for the diagnosis of lactose intolerance in a population from northeastern Brazil

OBJECTIVE: This work aimed to evaluate and correlate symptoms, biochemical blood test results and single nucleotide polymorphisms for lactose intolerance diagnosis. METHOD: A cross-sectional study was conducted in Fortaleza, Ceará, Brazil, with a total of 119 patients, 54 of whom were lactose intolerant. Clinical evaluation and biochemical blood tests were conducted after lactose ingestion and blood samples were collected for genotyping evaluation. In particular, the single nucleotide polymorphisms C>T-13910 and G>A-22018 were analyzed by restriction fragment length polymorphism/polymerase chain reaction and validated by DNA sequencing. RESULTS: Lactose-intolerant patients presented with more symptoms of flatulence (81.4%), bloating (68.5%), borborygmus (59.3%) and diarrhea (46.3%) compared with non-lactose-intolerant patients (p<0.05). We observed a significant association between the presence of the alleles T-13910 and A-22018 and the lactose-tolerant phenotype (p<0.05). After evaluation of the biochemical blood test results for lactose, we found that the most effective cutoff for glucose levels obtained for lactose malabsorbers was <15 mg/dL, presenting an area under the receiver operating characteristic curve greater than 80.3%, with satisfactory values for sensitivity and specificity. CONCLUSIONS: These data corroborate the association of these single nucleotide polymorphisms (C>T-13910 and G>A-22018) with lactose tolerance in this population and suggest clinical management for patients with lactose intolerance that considers single nucleotide polymorphism detection and a change in the biochemical blood test cutoff from <25 mg/dL to <15 mg/dL.

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Associations of HIV testing and late diagnosis at a Japanese university hospital

OBJECTIVES: This study was conducted to clarify the rate of late diagnosis of HIV infection and to identify relationships between the reasons for HIV testing and a late diagnosis. METHODS: This retrospective cohort study was conducted among HIV-positive patients at the Jikei University Hospital between 2001 and 2014. Patient characteristics from medical records, including age, sex, sexuality, the reason for HIV testing and the number of CD4-positive lymphocytes at HIV diagnosis, were assessed. RESULTS: A total of 459 patients (men, n=437; 95.2%) were included in this study and the median age at HIV diagnosis was 36 years (range, 18-71 years). Late (CD4 cell count <350/mm3) and very late (CD4 cell count <200/mm3) diagnoses were observed in 61.4% (282/459) and 36.6% (168/459) of patients, respectively. The most common reason for HIV diagnosis was voluntary testing (38.6%, 177/459 patients), followed by AIDS-defining illness (18.3%, 84/459 patients). Multivariate analysis revealed a significant association of voluntary HIV testing with non-late and non-very-late diagnoses and there was a high proportion of AIDS-defining illness in the late and very late diagnosis groups compared with other groups. Men who have sex with men was a relative factor for non-late diagnosis, whereas nonspecific abnormal blood test results, such as hypergammaglobulinemia and thrombocytopenia, were risk factors for very late diagnosis. CONCLUSIONS: Voluntary HIV testing should be encouraged and physicians should screen all patients who have symptoms or signs and particularly hypergammaglobulinemia and thrombocytopenia, that may nonspecifically indicate HIV infection.

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Analyses of balance and flexibility of obese patients undergoing bariatric surgery

OBJECTIVE: To assess the postural control and flexibility of obese subjects before and both six and 12 months after bariatric surgery. To verify whether postural control is related to flexibility following weight reductions resulting from bariatric surgery. METHODS: The sample consisted of 16 subjects who had undergone bariatric surgery. All assessments were performed before and six and 12 months after bariatric surgery. Postural balance was assessed using an Accusuway¯ portable force platform, and flexibility was assessed using a standard chair sit and reach test (Wells' chair). RESULTS: With the force platform, no differences were observed in the displacement area or velocity from the center of pressure in the mediolateral and anteroposterior directions. The displacement speed from the center of pressure was decreased at the six month after the surgery; however, unchanged from baseline at 12 months post-surgery. Flexibility increased over time according to the three measurements tested. CONCLUSIONS: Static postural balance did not change. The velocity of postural adjustment responses were increased at six months after surgery. Therefore, weight loss promotes increased flexibility. Yet, improvements in flexibility are not related to improvements in balance.

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Analysis of the Ki-67 index in the vaginal epithelium of castrated rats treated with tamoxifen

OBJECTIVES: Vaginal atrophy and breast cancer are common conditions in postmenopausal women and tamoxifen is the standard endocrine treatment for hormone-sensitive tumors. The present study aimed to assess the effect of tamoxifen on Ki-67 protein expression in the vaginal epithelium of castrated rats. MATERIAL AND METHODS: Forty Wistar-Hannover adult, virgin, castrated rats were randomly divided into two groups, group I (control, n=20) and group II (tamoxifen, n=20), receiving 0.5 ml of propylene glycol and 250 µg of tamoxifen diluted in 0.5 ml of propylene glycol, respectively, daily by gavage for 30 days. On the 31st day, the rats were euthanized and their vaginas were removed and fixed in 10% buffered formalin for the immunohistochemical study of Ki-67 protein expression. Data were analyzed by the Levene and Student's t tests (p<0.05). RESULTS: The mean index of Ki-67 expression in the rat vagina of groups I and II was 4.04±0.96 and 26.86±2.19, respectively (p<0.001). CONCLUSIONS: According to the results of the present study, tamoxifen, at the dose and treatment length used, induced a significant increase in the cell proliferation of the vaginal mucosa in castrated rats, as evaluated by Ki-67 protein expression.

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The efficacy and safety of urethral injection therapy for urinary incontinence in women: a systematic review

To evaluate the efficacy and safety of different bulking agents for treating urinary incontinence in women, a systematic review including only randomized controlled trials was performed. The subjects were women with urinary incontinence. The primary outcomes were clinical and urodynamic parameters. The results were presented as a weighted mean difference for non-continuous variables and as relative risk for continuous variables, both with 95% confidence intervals. Initially, 942 studies were identified. However, only fourteen eligible trials fulfilled the prerequisites. Altogether, the review included 1814 patients in trials of eight different types of bulking agents, and all studies were described and analyzed. The measured outcomes were evaluated using a large variety of instruments. The most common complications of the bulking agents were urinary retention and urinary tract infection. Additionally, there were certain major complications, such as one case of death after use of autologous fat. However, the lack of adequate studies, the heterogeneous populations studied, the wide variety of materials used and the lack of long-term follow-up limit guidance of practice. To determine which substance is the most suitable, there is a need for more randomized clinical trials that compare existing bulking agents based on standardized clinical outcomes.

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Spine radiosurgery for the local treatment of spine metastases: Intensity-modulated radiotherapy, image guidance, clinical aspects and future directions

Many cancer patients will develop spinal metastases. Local control is important for preventing neurologic compromise and to relieve pain. Stereotactic body radiotherapy or spinal radiosurgery is a new radiation therapy technique for spinal metastasis that can deliver a high dose of radiation to a tumor while minimizing the radiation delivered to healthy, neighboring tissues. This treatment is based on intensity-modulated radiotherapy, image guidance and rigid immobilization. Spinal radiosurgery is an increasingly utilized treatment method that improves local control and pain relief after delivering ablative doses of radiation. Here, we present a review highlighting the use of spinal radiosurgery for the treatment of metastatic tumors of the spine. The data used in the review were collected from both published studies and ongoing trials. We found that spinal radiosurgery is safe and provides excellent tumor control (up to 94% local control) and pain relief (up to 96%), independent of histology. Extensive data regarding clinical outcomes are available; however, this information has primarily been generated from retrospective and nonrandomized prospective series. Currently, two randomized trials are enrolling patients to study clinical applications of fractionation schedules spinal Radiosurgery. Additionally, a phase I clinical trial is being conducted to assess the safety of concurrent stereotactic body radiotherapy and ipilimumab for spinal metastases. Clinical trials to refine clinical indications and dose fractionation are ongoing. The concomitant use of targeted agents may produce better outcomes in the future.

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Clinical outcomes of osteonecrosis of the femoral head after autologous bone marrow stem cell implantation: a meta-analysis of seven case-control studies

The purpose of this study was to evaluate the clinical outcomes of osteonecrosis of the femoral head after autologous bone marrow stem cell implantation. We searched the PubMed, Embase and Web of Science databases and included all case-control trials that reported on the clinical outcomes of osteonecrosis progression, incidence of total hip arthroplasty and improvement in Harris hip scores. Overall, seven case-control trials were included. Compared with the controls, patients treated with the bone marrow stem cells implantation treatment showed improved clinical outcomes with delayed osteonecrosis progression (odds ratio = 0.17, 95% CI: 0.09 - 0.32; p <0.001), a lower total hip arthroplasty incidence (odds ratio = 0.30, 95% CI: 0.12 - 0.72; p <0.01) and increased Harris hip scores (mean difference = 4.76, 95% CI: 1.24 - 8.28; p<0.01). The heterogeneity, publication bias, and sensitivity analyses showed no statistical difference significant differences between studies. Thus, our study suggests that autologous bone marrow stem cells implantation has a good therapeutic effect on osteonecrosis of the femoral, resulting in beneficial clinical outcomes. However, trials with larger sample sizes are needed to confirm these findings.

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Simultaneous determination of estrogens (ethinylestradiol and norgestimate) concentrations in human and bovine serum albumin by use of fluorescence spectroscopy and multivariate regression analysis

Publication date: 15 May 2016
Source:Talanta, Volume 152
Author(s): LaQuana N. Hordge, Kiara L. McDaniel, Derick D. Jones, Sayo O. Fakayode
The endocrine disruption property of estrogens necessitates the immediate need for effective monitoring and development of analytical protocols for their analyses in biological and human specimens. This study explores the first combined utility of a steady-state fluorescence spectroscopy and multivariate partial-least-square (PLS) regression analysis for the simultaneous determination of two estrogens (17α-ethinylestradiol (EE) and norgestimate (NOR)) concentrations in bovine serum albumin (BSA) and human serum albumin (HSA) samples. The influence of EE and NOR concentrations and temperature on the emission spectra of EE-HSA EE-BSA, NOR-HSA, and NOR-BSA complexes was also investigated. The binding of EE with HSA and BSA resulted in increase in emission characteristics of HSA and BSA and a significant blue spectra shift. In contrast, the interaction of NOR with HSA and BSA quenched the emission characteristics of HSA and BSA. The observed emission spectral shifts preclude the effective use of traditional univariate regression analysis of fluorescent data for the determination of EE and NOR concentrations in HSA and BSA samples. Multivariate partial-least-squares (PLS) regression analysis was utilized to correlate the changes in emission spectra with EE and NOR concentrations in HSA and BSA samples. The figures-of-merit of the developed PLS regression models were excellent, with limits of detection as low as 1.6×10⁻⁸M for EE and 2.4×10⁻⁷M for NOR and good linearity (R²>0.994985). The PLS models correctly predicted EE and NOR concentrations in independent validation HSA and BSA samples with a root-mean-square-percent-relative-error (RMS%RE) of less than 6.0% at physiological condition. On the contrary, the use of univariate regression resulted in poor predictions of EE and NOR in HSA and BSA samples, with RMS%RE larger than 40% at physiological conditions. High accuracy, low sensitivity, simplicity, low-cost with no prior analyte extraction or separation required makes this method promising, compelling, and attractive alternative for the rapid determination of estrogen concentrations in biomedical and biological specimens, pharmaceuticals, or environmental samples.

Graphical abstract

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Mortality rates by occupation in Korea: a nationwide, 13-year follow-up study

Objective

The present study sought to identify inequalities in cause-specific mortality across different occupational groups in Korea.

Methods

The cohort included Korean workers enrolled in the national employment insurance programme between 1995 and 2000. Mortality was determined by matching death between 1995 and 2008 according to a nationwide registry of the Korea National Statistical Office. The cohort was divided into nine occupational groups according to the Korean Standard Occupational Classification (KSOC). Age-standardised mortality rates of each subcohort were calculated.

Results

The highest age-standardised mortality rate was identified in KSOC 6 (agricultural, forestry and fishery workers; male (M): 563.0 per 100 000, female (F): 206.0 per 100 000), followed by KSOC 9 (elementary occupations; M: 499.0, F: 163.4) and KSOC 8 (plant, machine operators and assemblers; M: 380.3, F: 157.8). The lowest rate occurred in KSOC 2 (professionals and related workers; M: 209.1, F: 93.3). Differences in mortality rates between KSOC 2 and KSOC 9 (M: 289.9, F: 70.1) and the rate ratio of KSCO9 to KSCO2 (M: 2.39, F: 1.75) were higher in men. The most prominent mortality rate difference was observed in external causes of death (M: 96.9, F: 21.6) and liver disease in men (38.3 per 100 000). Mental disease showed the highest rate ratio (M: 6.31, F: 13.00).

Conclusions

Substantial differences in mortality rates by occupation were identified. Main causes of death were injury, suicide and male liver disease. Development of policies to support occupations linked with a lower socioeconomic position should be prioritised.

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Correction for Singh et al., The Nectin-4/Afadin Protein Complex and Intercellular Membrane Pores Contribute to Rapid Spread of Measles Virus in Primary Human Airway Epithelia [Author Correction]

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Reply to "The Broadly Neutralizing, Anti-HIV Antibody 4E10: an Open and Shut Case?" [Letters to the Editor]

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Editorial Board [Masthead]

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Hemagglutinin Stalk Immunity Reduces Influenza Virus Replication and Transmission in Ferrets [Vaccines and Antiviral Agents]

We assessed whether influenza virus hemagglutinin stalk-based immunity protects ferrets against aerosol-transmitted H1N1 influenza virus infection. Immunization of ferrets by a universal influenza virus vaccine strategy based on viral vectors expressing chimeric hemagglutinin constructs induced stalk-specific antibody responses. Stalk-immunized ferrets were cohoused with H1N1-infected ferrets under conditions that permitted virus transmission. Hemagglutinin stalk-immunized ferrets had lower viral titers and delayed or no virus replication at all following natural exposure to influenza virus.

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Characterization of Antibody Bipolar Bridging Mediated by the Human Cytomegalovirus Fc Receptor gp68 [Virus-Cell Interactions]

The human cytomegalovirus glycoprotein gp68 functions as an Fc receptor for host IgGs and can form antibody bipolar bridging (ABB) complexes in which gp68 binds the Fc region of an antigen-bound IgG. Here we show that gp68-mediated endocytosis transports ABB complexes into endosomes, after which the complex is routed to lysosomes, presumably for degradation. These results suggest gp68 contributes to evasion of IgG-mediated immune responses by mediating destruction of host IgG and viral antigens.

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The Broadly Neutralizing, Anti-HIV Antibody 4E10: an Open and Shut Case? [Letters to the Editor]

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Analysis of Assembly and Budding of Lujo Virus [Virus-Cell Interactions]

The recently identified arenavirus Lujo virus (LUJV) causes fatal hemorrhagic fever in humans. We analyzed its mechanism of viral release driven by matrix protein Z and the cell surface glycoprotein precursor GPC. The L domains in Z are required for efficient virus-like particle release, but Tsg101, ALIX/AIP1, and Vps4A/B are unnecessary for budding. LUJV GPC is cleaved by site 1 protease (S1P) at the RKLM motif, and treatment with the S1P inhibitor PF-429242 reduced LUJV production.

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Isolation and Characterization of a Novel Bat Coronavirus Closely Related to the Direct Progenitor of Severe Acute Respiratory Syndrome Coronavirus [Genetic Diversity and Evolution]

We report the isolation and characterization of a novel bat coronavirus which is much closer to the severe acute respiratory syndrome coronavirus (SARS-CoV) in genomic sequence than others previously reported, particularly in its S gene. Cell entry and susceptibility studies indicated that this virus can use ACE2 as a receptor and infect animal and human cell lines. Our results provide further evidence of the bat origin of the SARS-CoV and highlight the likelihood of future bat coronavirus emergence in humans.

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Nonstructural 5A Protein of Hepatitis C Virus Regulates Soluble Resistance-Related Calcium-Binding Protein Activity for Viral Propagation [Virus-Cell Interactions]

Hepatitis C virus (HCV) is a major cause of chronic liver disease and is highly dependent on cellular proteins for virus propagation. To identify the cellular factors involved in HCV propagation, we recently performed protein microarray assays using the HCV nonstructural 5A (NS5A) protein as a probe. Of 90 cellular protein candidates, we selected the soluble resistance-related calcium-binding protein (sorcin) for further characterization. Sorcin is a calcium-binding protein and is highly expressed in certain cancer cells. We verified that NS5A interacted with sorcin through domain I of NS5A, and phosphorylation of the threonine residue 155 of sorcin played a crucial role in protein interaction. Small interfering RNA (siRNA)-mediated knockdown of sorcin impaired HCV propagation. Silencing of sorcin expression resulted in a decrease of HCV assembly without affecting HCV RNA and protein levels. We further demonstrated that polo-like kinase 1 (PLK1)-mediated phosphorylation of sorcin was increased by NS5A. We showed that both phosphorylation and calcium-binding activity of sorcin were required for HCV propagation. These data indicate that HCV modulates sorcin activity via NS5A protein for its own propagation.

IMPORTANCE Sorcin is a calcium-binding protein and regulates intracellular calcium homeostasis. HCV NS5A interacts with sorcin, and phosphorylation of sorcin is required for protein interaction. Gene silencing of sorcin impaired HCV propagation at the assembly step of the HCV life cycle. Sorcin is phosphorylated by PLK1 via protein interaction. We showed that sorcin interacted with both NS5A and PLK1, and PLK1-mediated phosphorylation of sorcin was increased by NS5A. Moreover, calcium-binding activity of sorcin played a crucial role in HCV propagation. These data provide evidence that HCV regulates host calcium metabolism for virus propagation, and thus manipulation of sorcin activity may represent a novel therapeutic target for HCV.

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Structure-Guided Redesign Increases the Propensity of HIV Env To Generate Highly Stable Soluble Trimers [Vaccines and Antiviral Agents]

Due to high viral diversity, an effective HIV-1 vaccine will likely require Envs derived from multiple subtypes to generate broadly neutralizing antibodies (bNAbs). Soluble Env mimics, like the native flexibly linked (NFL) and SOSIP trimers, derived from the subtype A BG505 Env, form homogeneous, stable native-like trimers. However, other Env sequences, such as JRFL and 16055 from subtypes B and C, do so to a lesser degree. The high-resolution BG505 SOSIP crystal structures permit the identification and redesign of Env elements involved in trimer stability. Here, we identified structure trimer-derived (TD) residues that increased the propensity of the subtype B JRFL and subtype C 16055 Env sequences to form well-ordered, homogenous, and highly stable soluble trimers. The generation of these spike mimics no longer required antibody-based selection, positive or negative. Using the redesigned subtype B and C trimer representatives as respective foundations, we further stabilized the NFL TD trimers by engineering an intraprotomer disulfide linkage in the prebridging sheet, I201C-A433C (CC), that locks the gp120 in the receptor nontriggered state. We demonstrated that this disulfide pair prevented CD4 induced-conformational rearrangements in NFL trimers derived from the prototypic subtype A, B, and C representatives. Coupling the TD-based design with the engineered disulfide linkage, CC, increased the propensity of Env to form soluble highly stable spike mimics that are resistant to CD4-induced changes. These advances will allow testing of the hypothesis that such stabilized immunogens will more efficiently elicit neutralizing antibodies in small-animal models and primates.

IMPORTANCE HIV-1 displays unprecedented global diversity circulating in the human population. Since the envelope glycoprotein (Env) is the target of neutralizing antibodies, Env-based vaccine candidates that address such diversity are needed. Soluble well-ordered Env mimics, typified by NFL and SOSIP trimers, are attractive vaccine candidates. However, the current designs do not allow most Envs to form well-ordered trimers. Here, we made design modifications to increase the propensity of representatives from two of the major HIV subtypes to form highly stable trimers. This approach should be applicable to other viral Envs, permitting the generation of a repertoire of homogeneous, highly stable trimers. The availability of such an array will allow us to assess if sequential or cocktail immune strategies can overcome some of the vaccine challenges presented by HIV diversity.

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Activation of RNase L by Murine Coronavirus in Myeloid Cells Is Dependent on Basal Oas Gene Expression and Independent of Virus-Induced Interferon [Pathogenesis and Immunity]

The oligoadenylate synthetase (OAS)-RNase L pathway is a potent interferon (IFN)-induced antiviral activity. Upon sensing double-stranded RNA, OAS produces 2',5'-oligoadenylates (2-5A), which activate RNase L. Murine coronavirus (mouse hepatitis virus [MHV]) nonstructural protein 2 (ns2) is a 2',5'-phosphodiesterase (PDE) that cleaves 2-5A, thereby antagonizing RNase L activation. PDE activity is required for robust replication in myeloid cells, as a mutant of MHV (ns2^H126R) encoding an inactive PDE fails to antagonize RNase L activation and replicates poorly in bone marrow-derived macrophages (BMM), while ns2^H126R replicates to high titer in several types of nonmyeloid cells, as well as in IFN receptor-deficient (Ifnar1^–/–) BMM. We reported previously that myeloid cells express significantly higher basal levels of OAS transcripts than nonmyeloid cells. Here, we investigated the contributions of Oas gene expression, basal IFN signaling, and virus-induced IFN to RNase L activation. Infection with ns2^H126R activated RNase L in Ifih1^–/– BMM to a similar extent as in wild-type (WT) BMM, despite the lack of IFN induction in the absence of MDA5 expression. However, ns2^H126R failed to induce RNase L activation in BMM treated with IFNAR1-blocking antibody, as well as in Ifnar1^–/– BMM, both expressing low basal levels of Oas genes. Thus, activation of RNase L does not require virus-induced IFN but rather correlates with adequate levels of basal Oas gene expression, maintained by basal IFN signaling. Finally, overexpression of RNase L is not sufficient to compensate for inadequate basal OAS levels.

IMPORTANCE The oligoadenylate synthetase (OAS)-RNase L pathway is a potent antiviral activity. Activation of RNase L during murine coronavirus (mouse hepatitis virus [MHV]) infection of myeloid cells correlates with high basal Oas gene expression and is independent of virus-induced interferon secretion. Thus, our data suggest that cells with high basal Oas gene expression levels can activate RNase L and thereby inhibit virus replication early in infection upon exposure to viral double-stranded RNA (dsRNA) before the induction of interferon and prior to transcription of interferon-stimulated antiviral genes. These findings challenge the notion that activation of the OAS-RNase L pathway requires virus to induce type I IFN, which in turn upregulates OAS gene expression, as well as to provide dsRNA to activate OAS. Our data further suggest that myeloid cells may serve as sentinels to restrict viral replication, thus protecting other cell types from infection.

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Neuropeptide Y Negatively Influences Monocyte Recruitment to the Central Nervous System during Retrovirus Infection [Pathogenesis and Immunity]

Monocyte infiltration into the CNS is a hallmark of several viral infections of the central nervous system (CNS), including retrovirus infection. Understanding the factors that mediate monocyte migration in the CNS is essential for the development of therapeutics that can alter the disease process. In the current study, we found that neuropeptide Y (NPY) suppressed monocyte recruitment to the CNS in a mouse model of polytropic retrovirus infection. NPY^–/– mice had increased incidence and kinetics of retrovirus-induced neurological disease, which correlated with a significant increase in monocytes in the CNS compared to wild-type mice. Both Ly6C^hi inflammatory and Ly6C^lo alternatively activated monocytes were increased in the CNS of NPY^–/– mice following virus infection, suggesting that NPY suppresses the infiltration of both cell types. Ex vivo analysis of myeloid cells from brain tissue demonstrated that infiltrating monocytes expressed high levels of the NPY receptor Y2R. Correlating with the expression of Y2R on monocytes, treatment of NPY^–/– mice with a truncated, Y2R-specific NPY peptide suppressed the incidence of retrovirus-induced neurological disease. These data demonstrate a clear role for NPY as a negative regulator of monocyte recruitment into the CNS and provide a new mechanism for suppression of retrovirus-induced neurological disease.

IMPORTANCE Monocyte recruitment to the brain is associated with multiple neurological diseases. However, the factors that influence the recruitment of these cells to the brain are still not well understood. In the current study, we found that neuropeptide Y, a protein produced by neurons, affected monocyte recruitment to the brain during retrovirus infection. We show that mice deficient in NPY have increased influx of monocytes into the brain and that this increase in monocytes correlates with neurological-disease development. These studies provide a mechanism by which the nervous system, through the production of NPY, can suppress monocyte trafficking to the brain and reduce retrovirus-induced neurological disease.

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Antibody Response to Hypervariable Region 1 Interferes with Broadly Neutralizing Antibodies to Hepatitis C Virus [Pathogenesis and Immunity]

Hypervariable region 1 (HVR1) (amino acids [aa] 384 to 410) on the E2 glycoprotein of hepatitis C virus contributes to persistent infection by evolving escape mutations that attenuate binding of inhibitory antibodies and by blocking access of broadly neutralizing antibodies to their epitopes. A third proposed mechanism of immune antagonism is that poorly neutralizing antibodies binding to HVR1 interfere with binding of other superior neutralizing antibodies. Epitope mapping of human monoclonal antibodies (HMAbs) that bind to an adjacent, conserved domain on E2 encompassing aa 412 to 423 revealed two subsets, designated HC33 HMAbs. While both subsets have contact residues within aa 412 to 423, alanine-scanning mutagenesis suggested that one subset, which includes HC33.8, has an additional contact residue within HVR1. To test for interference of anti-HVR1 antibodies with binding of antibodies to aa 412 to 423 and other E2 determinants recognized by broadly neutralizing HMAbs, two murine MAbs against HVR1 (H77.16) and aa 412 to 423 (H77.39) were studied. As expected, H77.39 inhibited the binding of all HC33 HMAbs. Unexpectedly, H77.16 also inhibited the binding of both subsets of HC33 HMAbs. This inhibition also was observed against other broadly neutralizing HMAbs to epitopes outside aa 412 to 423. Combination antibody neutralization studies by the median-effect analysis method with H77.16 and broadly reactive HMAbs revealed antagonism between these antibodies. Structural studies demonstrated conformational flexibility in this antigenic region, which supports the possibility of anti-HVR1 antibodies hindering the binding of broadly neutralizing MAbs. These findings support the hypothesis that anti-HVR1 antibodies can interfere with a protective humoral response against HCV infection.

IMPORTANCE HVR1 contributes to persistent infection by evolving mutations that escape from neutralizing antibodies to HVR1 and by shielding broadly neutralizing antibodies from their epitopes. This study provides insight into a new immune antagonism mechanism by which the binding of antibodies to HVR1 blocks the binding and activity of broadly neutralizing antibodies to HCV. Immunization strategies that avoid the induction of HVR1 antibodies should increase the inhibitory activity of broadly neutralizing anti-HCV antibodies elicited by candidate vaccines.

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Identification of a Human Respiratory Syncytial Virus Cell Entry Inhibitor by Using a Novel Lentiviral Pseudotype System [Virus-Cell Interactions]

Lentiviral budding is governed by group-specific antigens (Gag proteins) and proceeds in the absence of cognate viral envelope proteins, which has been exploited to create pseudotypes incorporating envelope proteins from nonlentiviral families. Here, we report the generation of infectious lentiviral pseudoparticles incorporating human respiratory syncytial virus (hRSV) F protein alone (hRSV-Fpp) or carrying SH, G, and F proteins (hRSV-SH/G/Fpp). These particles recapitulate key infection steps of authentic hRSV particles, including utilization of glycosaminoglycans and low-pH-independent cell entry. Moreover, hRSV pseudoparticles (hRSVpp) can faithfully reproduce phenotypic resistance to a small-molecule fusion inhibitor in clinical development (BMS-433771) and a licensed therapeutic F protein-targeting antibody (palivizumab). Inoculation of several human cell lines from lung and liver revealed more than 30-fold differences in susceptibility to hRSVpp infection, suggesting differential expression of hRSV entry cofactors and/or restriction factors between these cell types. Moreover, we observed cell-type-dependent functional differences between hRSVpp carrying solely F protein or SH, G, and F proteins with regard to utilization of glycosaminoglycans. Using hRSVpp, we identified penta-O-galloyl-β-d-glucose (PGG) as a novel hRSV cell entry inhibitor. Moreover, we show that PGG also inhibits cell entry of hRSVpp carrying F proteins resistant to BMS-433771 or palivizumab. This work sheds new light on the mechanisms of hRSV cell entry, including possible strategies for antiviral intervention. Moreover, hRSVpp should prove valuable to dissect hRSV envelope protein functions, including the interaction with cell entry factors.

IMPORTANCE Lentiviral pseudotypes are highly useful to specifically dissect the functions of viral and host factors in cell entry, which have been exploited for numerous viruses. Here, we successfully created hRSVpp and show that they faithfully recapitulate key characteristics of parental hRSV cell entry. Importantly, hRSVpp accurately mirror hRSV resistance to small-molecule fusion inhibitors and clinically approved therapeutic antibodies. Moreover, we observed highly different susceptibilities of cell lines to hRSVpp infection and also differences between hRSVpp types (with F protein alone or with SH, G, and F proteins) in regard to cell entry. This indicates differential expression of host factors determining hRSV cell entry between these cell lines and highlights the fact that the hRSVpp system is useful to explore the functional properties of hRSV envelope protein combinations. Therefore, this system will be highly useful to study hRSV cell entry and host factor usage and to explore antiviral strategies targeting hRSV cell entry.

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